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1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(9): 1009-1015, 2019 Sep 28.
Artigo em Chinês | MEDLINE | ID: mdl-31645490

RESUMO

OBJECTIVE: To investigate the experience and efficacy of endoscopic thyroidectomy for papillary thyroid microcarcinoma (PTMC) through total areola approach.
 Methods: A total of 117 PTMC patients, who were diagnosed pathologically in Minimally Invasive Surgical Center, Second Xiangya Hospital, Central South University from June 2016 to December 2017, were divided into a endoscopic surgery group (n=72) and an open surgery group (n=45). The number of dissected central lymph nodes, blood loss, amount of drainage, occurrence of postoperative complication and recurrence were collected and compared.
 Results: Compared with the open surgery group, the blood loss was less and the operative time was longer in the endoscopic surgery group (P<0.05). There were no significant differences between the 2 groups in the number of dissected central lymph nodes, amount of drainage and occurrence of postoperative complication (all P>0.05). The mean follow-up time was more than 20 months, and there was no recurrence in the 2 groups. 
 Conclusion: Endoscopic thyroidectomy with central compartment neck dissection through total areola approach is safe and feasible in patients with PTMC. It has many advantages, such as no scar on neck, less blood loss, shorter hospital stay and more acceptable to young patients.

2.
J Agric Food Chem ; 67(42): 11568-11576, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31584809

RESUMO

Tribenuron-methyl (TM), as one of the sulfonylurea (SU) herbicides, has been widely and effectively applied for many kinds of plants. SUs inhibit plant growth by restraining the biosynthetic pathway of branched-chain amino acids (BCAAs) catalyzed by acetolactate synthase (ALS). Safeners are agrochemicals that protect crops from herbicide injuries. To improve the crop tolerance under TM toxicity stress, this paper evaluated the protective effect of N-tosyloxazolidine-3-carboxamide. It turned out that most of the tested compounds showed significant protection against TM via enhancing the glutathione (GSH) content and glutathione S-transferase (GST) activity. Among all of the tested compounds, compound 16 exhibited more excellent protection than the contrast safener R-28725 and other target compounds. A positive correlation between the growth level, endogenous GSH content, and GST activity was observed in this research. The GST kinetic parameter Vmax of the maize was increased by 29.6% after treatment with compound 16, while Km was decreased by 51.9% compared to the untreated control. The molecular docking model indicated that compound 16 could compete with TM in the active site of ALS, which could interpret the protective effects of safeners. The present work demonstrated that N-tosyloxazolidine-3-carboxamide derivatives could be considered as potential candidates for developing new safeners in the future.

3.
J Mol Diagn ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31605803

RESUMO

A quantitative chimerism test monitors engraftment of donor hematopoietic stem cells or relapse of leukemias or lymphomas in hematopoietic stem cell transplantation patients. The most common method used for chimerism testing is PCR amplification of short tandem repeat loci followed by capillary gel electrophoresis. Manual data analysis is tedious and time consuming, as it involves the selection of informative loci and the repetition of quantifying chimerism percentage for multiple loci from multiple cell types. It is also susceptible to human errors. Currently, there is no free software to fully automate chimerism data analysis. Rchimerism, an R shiny package, was developed to automatically pick informative loci, calculate chimerism percentage, and display the results through a user-friendly interface. The accuracy of the program was compared with manual calculation on 60 patient samples with 100% concordance. Compared to manual calculation, Rchimerism drastically reduces analysis time from 20 to 40 minutes for single donor transplantation samples and 40 to 80 minutes for double donor transplantation samples to less than one minute. Rchimerism can be downloaded and used freely by non-commercial laboratories.

4.
Aesthet Surg J ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31606742

RESUMO

BACKGROUND: The dimensions of the nipple-areolar complex (NAC) and its location on the chest wall are important aesthetic factors in male breast surgery. OBJECTIVES: This study examines the perceptions of aesthetic surgeons and the general population for the aesthetically ideal position and size of male NAC. METHODS: An online survey was distributed to the American Society for Aesthetic Plastic Surgery (ASAPS) members and to the general population. Parameters queried included demographics for all participants, and academic details for ASAPS members. Both surveys included a male model picture with 16 separate choices for the NAC position from a frontal view, 5 choices for the NAC position from a lateral view, and 6 choices for the NAC dimensions. For all three sets of images, the participants were asked to rank the top three images they considered most "aesthetically pleasing" in descending order. A weighted scoring rule was created to quantitatively evaluate image choices. Standard statistical methods were used for analysis. RESULTS: The survey was completed by 272 ASAPS members and 4909 participants from the general population. The top three choices for NAC location on frontal view were the same for ASAPS members and the general population. The most popular NAC location on lateral view was the same for both groups, but the preferred locations were different between the two groups for the second and third choices. The most popular dimensions of the NAC were 2 cm (vertical) x 3 cm (horizontal) followed by 2 cm x 2 cm for both groups. Comparison of the three top image choices scores between different ethnic groups and individuals with different gender or sexual orientation demonstrated similar trends. CONCLUSION: This survey identified the preferred position and dimensions of the NAC on the male breast for plastic surgeons and the general population. These parameters should be taken into consideration when counseling males undergoing breast surgery.

5.
Med Sci Monit ; 25: 7808-7812, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31624224

RESUMO

BACKGROUND The aim of this study was to investigate the correlations of circadian rhythm disorder of blood pressure with arrhythmia and target organ damage in hypertensive patients. MATERIAL AND METHODS A total of 198 patients admitted and treated in our hospital from May 2018 to April 2019 were selected to receive 24-h ambulatory blood pressure monitoring. The nighttime blood pressure decrease rate is 0-10% in people with normal circadian rhythm of blood pressure. In the present study, we divided patients into a normal circadian rhythm group (normal circadian rhythm of blood pressure, n=132) and a circadian rhythm disorder group (circadian rhythm disorder of blood pressure, n=66) according to the circadian rhythm of blood pressure. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean pulse pressure (PP) were observed, and dynamic electrocardiography was performed to observe the status of arrhythmia. Finally, the degree of damage to target organs such as heart, brain, and kidney was compared. RESULTS The circadian rhythm disorder group had remarkably higher daytime SBP (d-SBP), daytime DBP (d-DBP), and daytime PP (d-PP) but clearly lower nighttime SBP (n-SBP), nighttime DBP (n-DBP), and nighttime PP (n-PP) than in the normal circadian rhythm group (P<0.0001). The detection rate of arrhythmia and the degree of target organ damage were clearly higher in the circadian rhythm disorder group compared with the normal circadian rhythm group (P<0.0001). Moreover, the incidence rates of heart disease, cerebrovascular disease, and nephropathy were higher in the circadian rhythm disorder group than in the normal circadian rhythm group (P<0.0001). CONCLUSIONS The circadian rhythm disorder of blood pressure in hypertensive patients probably increases the risk of arrhythmia and worsens the target organ damage, so attention should be paid to the adjustment of disordered blood pressure rhythm in hypertensive patients in clinical practice.

6.
RNA Biol ; : 1-8, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31607216

RESUMO

Non-coding RNAs occupy a significant fraction of the human genome. Their biological significance is backed up by a plethora of emerging evidence. One of the most robust approaches to demonstrate non-coding RNA's biological relevance is through their prognostic value. Using the rich gene expression data from The Cancer Genome Altas (TCGA), we designed Advanced Expression Survival Analysis (AESA), a web tool which provides several novel survival analysis approaches not offered by previous tools. In addition to the common single-gene approach, AESA computes the gene expression composite score of a set of genes for survival analysis and utilizes permutation test or cross-validation to assess the significance of log-rank statistic and the degree of over-fitting. AESA offers survival feature selection with post-selection inference and utilizes expanded TCGA clinical data including overall, disease-specific, disease-free, and progression-free survival information. Users can analyse either protein-coding or non-coding regions of the transcriptome. We demonstrated the effectiveness of AESA using several empirical examples. Our analyses showed that non-coding RNAs perform as well as messenger RNAs in predicting survival of cancer patients. These results reinforce the potential prognostic value of non-coding RNAs. AESA is developed as a module in the freely accessible analysis suite MutEx. Abbreviation: ACC: Adrenocortical Carcinoma (n = 92); BLCA: Bladder Urothelial Carcinoma (n = 412); BRCA: Breast Invasive Carcinoma (n = 1098); CESC: Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (n = 307); CHOL: Cholangiocarcinoma (n = 51); COAD: Colon Adenocarcinoma (n = 461); DLBC: Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (n = 58); ESCA: Oesophageal Carcinoma (n = 185); GBM: Glioblastoma Multiforme (n = 617); HNSC: Head and Neck Squamous Cell Carcinoma (n = 528); KICH: Kidney Chromophobe (n = 113); KIRC: Kidney Renal Clear Cell Carcinoma (n = 537); KIRP: Kidney Renal Papillary Cell Carcinoma (n = 291); LAML: Acute Myeloid Leukaemia (n = 200); LGG: Brain Lower Grade Glioma (n = 516); LIHC: Liver Hepatocellular Carcinoma (n = 377); LUAD: Lung Adenocarcinoma (n = 585); LUSC: Lung Squamous Cell Carcinoma (n = 504); MESO: Mesothelioma (n = 87); OV: Ovarian Serous Cystadenocarcinoma (n = 608) PAAD: Pancreatic Adenocarcinoma (n = 185); PCPG: Pheochromocytoma and Paraganglioma (n = 179); PRAD: Prostate Adenocarcinoma (n = 500); READ: Rectum Adenocarcinoma (n = 172); SARC: Sarcoma (n = 261); SKCM: Skin Cutaneous Melanoma (n = 470); STAD: Stomach Adenocarcinoma (n = 443); TGCT: Testicular Germ Cell Tumours (n = 150); THCA: Thyroid Carcinoma (n = 507) THYM: Thymoma (n = 124); UCEC: Uterine Corpus Endometrial Carcinoma (n = 560); UCS: Uterine Carcinosarcoma (n = 57); UVM: Uveal Melanoma (n = 80).

7.
Brief Bioinform ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588509

RESUMO

Somatic mutation and gene expression dysregulation are considered two major tumorigenesis factors. While independent investigations of either factor pervade, studies of associations between somatic mutations and gene expression changes have been sporadic and nonsystematic. Utilizing genomic data collected from 11 315 subjects of 33 distinct cancer types, we constructed MutEx, a pan-cancer integrative genomic database. This database records the relationships among gene expression, somatic mutation and survival data for cancer patients. MutEx can be used to swiftly explore the relationship between these genomic/clinic features within and across cancer types and, more importantly, search for corroborating evidence for hypothesis inception. Our database also incorporated Gene Ontology and several pathway databases to enhance functional annotation, and elastic net and a gene expression composite score to aid in survival analysis. To demonstrate the usability of MutEx, we provide several application examples, including top somatic mutations associated with the most extensive expression dysregulation in breast cancer, differential mutational burden downstream of DNA mismatch repair gene mutations and composite gene expression score-based survival difference in breast cancer. MutEx can be accessed at http://www.innovebioinfo.com/Databases/Mutationdb_About.php.

8.
Acta Pharmacol Sin ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659239

RESUMO

Osteocalcin, expressed in osteoblasts of the bone marrow, undergoes post-translational carboxylation and deposits in mineralized bone matrix. A portion of osteocalcin remains uncarboxylated (uncarboxylated osteocalcin, GluOC) that is released into blood where it functions as a hormone to regulate insulin secretion and insulin sensitivity. As insulin resistance is closely associated with metabolic syndrome, this study is aimed to elucidate how GluOC regulates glucose and lipid metabolism in KKAy mice, an animal model displaying obese, hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. GluOC (3, 30 ng/g per day, ig) was orally administered to female KKAy mice for 4 weeks. Whole-body insulin sensitivity, glucose metabolism, hepatic steatosis, dyslipidemia were examined using routine laboratory assays. We found that GluOC administration significantly enhanced insulin sensitivity in KKAy mice by activating hepatic IRß/PI3K/Akt pathway and elevated the whole-body insulin sensitivity with decreased FPI and HOMA-IR index. Furthermore, GluOC administration alleviated hyperglycemia through suppressing gluconeogenesis and promoting glycogen synthesis in KKAy mice and in cultured hepatocytes in vitro. Moreover, GluOC administration dose-dependently ameliorated dyslipidemia and attenuated hepatic steatosis in KKAy mice by inhibiting hepatic de novo lipogenesis and promoting fatty-acid ß-oxidation. These results demonstrate that GluOC effectively enhances hepatic insulin sensitivity, improves hyperglycemia and ameliorates hepatic steatosis in KKAy mice, suggesting that GluOC could be a promising drug candidate for treating metabolic syndrome.

9.
J Agric Food Chem ; 67(43): 11839-11847, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31589436

RESUMO

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an important target site for discovering new bleaching herbicides. To explore novel HPPD inhibitors with excellent herbicidal activity, a series of novel N-aroyl diketone/triketone derivatives were rationally designed by splicing active groups and bioisosterism. Bioassays revealed that most of these derivatives displayed preferable herbicidal activity against Echinochloa crus-galli (EC) at 0.045 mmol/m2 and Abutilon juncea (AJ) at 0.090 mmol/m2. In particular, compound I-f was more potent compared to the commercialized compound mesotrione. Molecular docking indicated that the corresponding active molecules of target compounds and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD.

10.
Cell Oncol (Dordr) ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520395

RESUMO

BACKGROUND: Protein arginine methyltransferase 1 (PRMT1) is the founding member of the PRMT family of proteins, whose members catalyze methylation of arginine residues in various proteins. Although several studies have reported upregulation of PRMT1 in various cancer types, the expression pattern and the underlying mechanism of PRMT1 action in pancreatic ductal adenocarcinoma (PDAC) are still unclear. METHODS: Immunohistochemistry staining as well as RT-PCR was used to determine the expression pattern of PRMT1 in clinical PDAC samples. Lentivirus packaging and transfection were employed to construct cell lines with PRMT1 overexpression or knockdown. MTT and crystal violet assays were used to determine the proliferation rates of PDAC cells. ß-catenin transcription activity was measured using a TOPFlash assay. PRMT1 binding to the promoter region of CTNNB1 was determined by ChIP-qPCR assay. RESULTS: Elevated PRMT1 expression was found in PDAC tissue samples compared to noncancerous normal tissues in 41 patients using a real-time PCR assay and in 90 patients using a tissue microarray (TMA) in conjunction with immunohistochemistry. Analysis of the PRMT1 expression data and PDAC clinical features revealed that PRMT1 expression was significantly correlated with PDAC tumor size and prognosis in postoperative patients. Additional functional experiments revealed that PRMT1 expression promoted the growth of pancreatic cancer-derived cells, both in vitro and in vivo. Mechanistically, we found that PRMT1 increased the cellular ß-catenin level. We also found that PRMT1 and ß-catenin were co-expressed in TCGA and GTEx datasets containing 370 samples. CONCLUSIONS: Collectively, our study provides novel insight into the expression and function of PRMT1 in PDAC and indicates that PRMT1 may serve as a therapeutic target for treating patients with pancreatic ductal adenocarcinoma.

11.
Pharmacol Ther ; : 107406, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521697

RESUMO

Epigenetics has emerged as an extremely exciting fast-growing area of biomedical research in post genome era. Epigenetic dysfunction is tightly related with various diseases such as cancer and aging related degeneration, potentiating epigenetics modulators as important therapeutics targets. Indeed, inhibitors of histone deacetylase and DNA methyltransferase have been approved for treating blood tumor malignancies, whereas inhibitors of histone methyltransferase and histone acetyl-lysine recognizer bromodomain are in clinical stage. However, it remains a great challenge to discover potent and selective inhibitors by targeting catalytic site, as the same subfamily of epigenetic enzymes often share high sequence identity and very conserved catalytic core pocket. It is well known that epigenetic modifications are usually carried out by multi-protein complexes, and activation of catalytic subunit is often tightly regulated by other interactive protein component, especially in disease conditions. Therefore, it is not unusual that epigenetic complex machinery may exhibit allosteric regulation site induced by protein-protein interactions. Targeting allosteric site emerges as a compelling alternative strategy to develop epigenetic drugs with enhanced druggability and pharmacological profiles. In this review, we highlight recent progress in the development of allosteric inhibitors for epigenetic complexes through targeting protein-protein interactions. We also summarized the status of clinical applications of those inhibitors. Finally, we provide perspectives of future novel allosteric epigenetic machinery modulators emerging from otherwise undruggable single protein target.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31562112

RESUMO

OBJECTIVE: We evaluated the prognostic value of lymph node ratio (LNR) for the survival of breast cancer patients using Bayesian inference. METHODS: Data on 5,279 women with infiltrating duct and lobular carcinoma breast cancer, diagnosed from 2006-2010, was obtained from the NCI SEER Cancer Registry. A prognostic modeling framework was proposed using Bayesian inference to estimate the impact of LNR in breast cancer survival. Based on the proposed model, we then developed a web application for estimating LNR and predicting overall survival. RESULTS: The final survival model with LNR outperformed the other models considered (C-statistic 0.71). Compared to directly measured LNR, estimated LNR slightly increased the accuracy of the prognostic model. Model diagnostics and predictive per- formance confirmed the effectiveness of Bayesian modeling and the prognostic value of the LNR in predicting breast cancer survival. CONCLUSION: The estimated LNR was found to have a significant predictive value for the overall survival of breast cancer patients. SIGNIFICANCE: We used Bayesian inference to estimate LNR which was then used to predict overall survival. The models were developed from a large population-based cancer registry. We also built a user-friendly web application for individual patient survival prognosis. The diagnostic value of the LNR and the effectiveness of the proposed model were evaluated by comparisons with existing prediction models.

13.
Biomolecules ; 9(10)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547161

RESUMO

The herbicide fomesafen has the advantages of low toxicity and high selectivity, and the target of this compound is protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4). However, this herbicide has a long residual period and can have phytotoxic effects on succeeding crops. To protect maize from fomesafen, a series of thiazole phenoxypyridines were designed based on structure-activity relationships, active substructure combinations, and bioisosterism. Bioassays showed that thiazole phenoxypyridines could improve maize tolerance under fomesafen toxicity stress to varying degrees at a dose of 10 mg·kg-1. Compound 4i exhibited the best effects. After being treated by compound 4i, average recovery rates of growth index exceeded 72%, glutathione content markedly increased by 167% and glutathione S-transferase activity was almost 163% of fomesafen-treated group. More importantly, after being treated by compound 4i, the activity of PPO, the main target enzyme of fomesafen, recovered to 93% of the control level. The molecular docking result exhibited that the compound 4i could compete with fomesafen to bind with the herbicide target enzyme, which consequently attained the herbicide detoxification. The present work suggests that compound 4i could be developed as a potential safener to protect maize from fomesafen.

14.
Herz ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31555892

RESUMO

BACKGROUND: Our study analyzed the relationship between the neointimal strut bridge and jailed side-branch (SB) ostial area in patients with coronary heart disease (CHD) who had a single drug-eluting stent (DES) crossover of the left anterior descending coronary artery (LAD)/diagonal branch (D) bifurcation. PATIENTS AND METHODS: A total of 64 CHD patients with an LAD/D bifurcation treated by optical coherence tomography (OCT)-guided single-DES implantation and followed up at 1 year after primary percutaneous intervention (pPCI) were enrolled in our study. According to the two-dimensional OCT results, patients were divided into a non-neointimal bridge group (n = 44) and a neointimal bridge group (n = 20). Basic clinical, angiographic, 2D and 3D OCT, and DES results were analyzed. RESULTS: The blood lipid levels of the two groups after the 1­year follow-up were lower than the levels 1 year earlier (p < 0.05). There was a notable decrease in the SB ostial minimum lumen diameter and area directly after pPCI vs. before pPCI in both groups. The diameter stenosis directly after pPCI showed a clear increase compared with the pre-pPCI value in both groups (p < 0.05 or p < 0.01, respectively). The strut distance of the neointimal bridges in the neointimal bridge group was greater than in the non-neointimal bridge group (p < 0.05). A clearly short strut distance of the neointimal bridge was observed compared with the strut distance of the non-neointimal bridge in the neointimal bridge group (p < 0.05). A larger neointimal bridge area and a smaller SB ostial area were found in the neointimal bridge group compared with the non-neointimal bridge group (p < 0.05 or p < 0.01, respectively). CONCLUSION: A short strut distance facilitated formation of a neointimal bridge, which significantly influenced the SB ostial area after single crossover stenting of the SB orifice at the 1­year follow-up.

15.
ACS Nano ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31553178

RESUMO

Although Sn-Pb perovskites sensing near-ultraviolet-visible-near-infrared light could be an attractive alternative to silicon in photodiodes and imaging, there have been no clear studies on such devices constructed on metal/silicon substrates, hindering their direct integration with complementary metal-oxide semiconductor (CMOS) and silicon electronics. Typically, high surface roughness and severe pinholes of Sn-rich binary perovskites make it difficult for them to fulfill the requirements of efficient photodiodes and imaging. These issues cause inherently high dark current and poor (dark and photo-) current uniformity. Herein, we propose and demonstrate the room-temperature crystallization in the Sn-rich binary perovskite system to effectively control film crystallization kinetics. With experimental and theoretical studies of the crystallization mechanism, we successfully tune the density and location of nanocrystals in precursor films to achieve compact nanocrystals, which coalesce into high-quality (smooth, dense, and pinhole-free) perovskites with intensified preferred orientation and decreased trap density. The high-quality perovskites reduce dark current and improve (dark and photo-) current uniformity of perovskite photodiodes on CMOS-compatible metal/silicon substrates. Meanwhile, self-powered devices achieve a high responsivity of 0.2 A/W at 940 nm, a large dynamic range of 100 dB, and a fast fall time of 2.27 µs, exceeding those of most silicon-based imaging sensors. Finally, a 6 × 6 pixel integrated photodiode array is successfully demonstrated to realize the imaging application. The work contributes to understanding the fundamentals of the crystallization of Sn-rich binary perovskites and advancing perovskite integration with Si-based electronics.

16.
Gene ; 721: 144093, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31473323

RESUMO

Previous studies have determined that long non-coding RNA (lncRNA) Fer-1-like protein 4 (FER1L4) is suppressed in osteosarcoma (OS) and inhibits the tumorigenesis in a variety of cancer. However, the precise biological of FER1L4 in OS has not been cleared. The aim of this study is to investigate the roles and potential mechanisms of FER1L4 in apoptosis and epithelial-mesenchymal transition (EMT) in OS. In the present study, the levels of FER1L4 were decreased significantly in OS tissues and cell lines compared with non-tumorous tissues or hFOB1.19. Knockdown of FER1L4 in OS cells decreased the apoptosis rate, but increased the OS cell proliferation, upregulated the expression levels of CD133 and Nanog, as well as promoted Twist1 expression, increased the N-cadherin and Vimentin expression. In turn, the opposite trends were observed upon overexpression of FER1L4. In addition, the expression of PI3K, p-AKT (Ser470) and p-AKT (Thr308) was upregulated by siFER1L4, while decreased upon overexpression of FER1L4. MicroRNA (miRNA) -18a-5p, an osteosarcoma-promoting miRNA which was suggested a target of FER1L4 in osteosarcoma, was identified to be a functional target of FER1L4 on the regulating of cell apoptosis and EMT, presently. The effects of FER1L4 overexpression on the markers of cell apoptosis, proliferation, EMT, and stemness and PI3K/AKT signaling were all reversed by miR-18a-5p upregulation. Furthermore, the suppressor of cytokine signaling 5 (SOCS5) was confirmed a target gene of miR-18a-5p by luciferase gene reporter assay and SOCS5 suppression by miR-18a-5p attenuated the effects of FER1L4 overexpression on the OS cells apoptosis and the expressed levels of PI3K, AKT, Twist1, N-cadherin and Vimentin. In conclusion, our data indicated thatthe overexpression of FER1L4 promoted apoptosis and inhibited the EMT markers expression and PI3K/AKT signaling pathway activation in OS cells via downregulating miR-18a-5p to promote SOCS5.

17.
Neuron ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31492534

RESUMO

Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) modulate AMPAR synaptic trafficking and transmission via disc-large (DLG) subfamily of membrane-associated guanylate kinases (MAGUKs). Despite extensive studies, the molecular mechanism governing specific TARP/MAGUK interaction remains elusive. Using stargazin and PSD-95 as the representatives, we discover that the entire tail of stargazin (Stg_CT) is required for binding to PSD-95. The PDZ binding motif (PBM) and an Arg-rich motif upstream of PBM conserved in TARPs bind to multiple sites on PSD-95, thus resulting in a highly specific and multivalent stargazin/PSD-95 complex. Stargazin in complex with PSD-95 or PSD-95-assembled postsynaptic complexes form highly concentrated and dynamic condensates via phase separation, reminiscent of stargazin/PSD-95-mediated AMPAR synaptic clustering and trapping. Importantly, charge neutralization mutations in TARP_CT Arg-rich motif weakened TARP's condensation with PSD-95 and impaired TARP-mediated AMPAR synaptic transmission in mice hippocampal neurons. The TARP_CT/PSD-95 interaction mode may have implications for understanding clustering of other synaptic transmembrane proteins.

18.
Int J Mol Sci ; 20(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554226

RESUMO

Selenocompounds (SeCs) are well-known nutrients and promising candidates for cancer therapy; however, treatment efficacy is very heterogeneous and the mechanism of action is not fully understood. Several SeCs have been reported to have albumin-binding ability, which is an important factor in determining the treatment efficacy of drugs. In the present investigation, we hypothesized that extracellular albumin might orchestrate SeCs efficacy. Four SeCs representing distinct categories were selected to investigate their cytotoxicity, cellular uptake, and species transformation. Concomitant treatment of albumin greatly decreased cytotoxicity and cellular uptake of SeCs. Using both X-ray absorption spectroscopy and hyphenated mass spectrometry, we confirmed the formation of macromolecular conjugates between SeCs and albumin. Although the conjugate was still internalized, possibly via albumin scavenger receptors expressed on the cell surface, the uptake was strongly inhibited by excess albumin. In summary, the present investigation established the importance of extracellular albumin binding in determining SeCs cytotoxicity. Due to the fact that albumin content is higher in humans and animals than in cell cultures, and varies among many patient categories, our results are believed to have high translational impact and clinical implications.

20.
Angew Chem Int Ed Engl ; 58(45): 16161-16166, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31475767

RESUMO

Herein, we report a two-step process forming arene C-O bonds in excellent site-selectivity at a late-stage. The C-O bond formation is achieved by selective introduction of a thianthrenium group, which is then converted into C-O bonds using photoredox chemistry. Electron-rich, -poor and -neutral arenes as well as complex drug-like small molecules are successfully transformed into both phenols and various ethers. The sequence differs conceptually from all previous arene oxygenation reactions in that oxygen functionality can be incorporated into complex small molecules at a late stage site-selectively, which has not been shown via aryl halides.

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